The combination of gemcitabine + platinum (either
cisplatin, carboplatin, or oxaliplatin) is the most important drug combination
introduced for the treatment of solid tumors in the past 15 years. We have
observed clinical responses with this regimen which are, to my knowledge,
unprecedented. A complete remission and 6 year history of enduring remission in
a patient
with unresectable pancreatic adenocarcinoma metastatic to spleen, kidney, and
omentum . A complete remission and greater than 4 year survival in a
patient with massive, non-cytoreducible ovarian cancer who had primary
progression on platinum/Taxol, followed by progressive disease despite tandem
high dose chemotherapy and tandem stem cell transplants at a cost of more than
$200,000. A clinical complete remission in a patient with colon cancer
metastatic to liver and lungs (large "cannonball" lesions), following failure of
adjuvant 5FU/levamisole, 5FU/leucovorin, 9-aminocamptothecin, and
biotherapy. A durable, complete remission (lasting years) in a patient
with gastric cancer metastatic to nodes and liver. And many others.

We began Cell Culture Drug Resistance Testing (CCDRT) of
the gemcitabine + cisplatin combination in the mid-90s at the specific
suggestion of Dr. Robert Nagourney, Director of Rational Therapeutics,Inc. . At the
time, it was a virtually unexplored combination, and many patients received
treatment with this regimen because of our CCDRT results long before any
clinical trials in their particular disease types had ever been published.
Dr. Nagourney's contributions in terms of recognizing the profound synergy of
this combination and promoting the use of this combination have been very
important in getting clinical trials with this regimen started in a broad
spectrum of cancers. In our experience, gemcitabine + platinum combinations are
the most synergistic drug
combinations in solid tumors which we have ever tested.

I believe that the most probable mechanism for the
profound synergy between gemcitabine + platinum is gemcitabine inhibition of
repair of platinum/DNA adducts. Basically, platinum-resistant tumor cells "cut
out" the damaged DNA (to which the platinum is attached) in the same way that
the railroad company repairs damaged sections of rail track. Then the
railroad company lays down new track. Platinum-resistant tumor cells do
the same thing, and gemcitabine interferes with this process. Thus, you
want to administer first gemcitabine (to have gemcitabine on board to inhibit
the repair process). Then, you want to administer platinum shortly
thereafter. In addition, you don't want to give either gemcitabine or
platinum by itself on any days of the cycle; this doesn't take advantage of the
synergy between the drugs and, in many cases, will just increase
toxicity.

As just one example of how clinical oncologists too
often get this wrong, there is a study just published in the current issue of
Gynecologic Oncology, by a team of French and Belgian investigators (Belpomme,
et al. Gemcitabine combined with cisplatin as first-line treatment in patients
with epithelial ovarian cancer: a phase II study. Gynecol. Oncol. 91:32-38,
2003).

In the above study, patients with previously-untreated
ovarian cancer were treated with gemcitabine plus cisplatin. Patients
received cisplatin 75 mg/M2 on Day 1 and gemcitabine 1250 mg/M2 on Days 1
(after cisplatin) and Day 8 (by itself, without cisplatin) of a 21
day treatment cycle. The results were decidedly ordinary (about the same which
would be expected with single agent platinum alone). Overall response rate
of 65%. Median survival of 24 months.

The above results were entirely predictable, as the
investigators did not design their treatment schedule to take advantage of the
profound gemcitabine/platinum synergy which does exist when platinum is
administered in the presence of gemcitabine.

In cases where CCDRT identifies
gemcitabine/platinum as the in vitro best regimen, I personally recommend to all
of our referring oncologists the below-described treatment schedules of
gemcitabine/cisplatin and gemcitabine/carboplatin, designed 7 years ago by Dr.
Dwight McKee:

Amifostine may reduce platinum toxicity, including the thrombocytopenia with
gemcitabine + carboplatin, but has the disadvantage of being emetogenic, if
given without anti-emetic premedication or if given after the anti-emetic
effects of premedications have dissipated. If amifostine is administered,
care must be taken regarding the timing of antiemetic premedication. - -
- -

Gemcitabine/Cisplatin/Amifostine Protocol

Day One:

Ondansetron hydrochloride 32 mg IV + dexamethasone 10 mg IV + cimetidine
300 mg IV + diphenhydramine 25 - 50 mg IV (these are medications to reduce
nausea and vomiting); then immediately give gemcitabine 1 gram/M2 IV over 45
- 60 minutes* and at the same time gemcitabine is started also start to give
hydration with one liter of 0.9% NaCl over one hour. Then administer
amifostine 740 mg/M2 over 10 minutes, monitoring the blood pressure
carefully and interrupting the infusion for a drop of systolic blood
pressure >> 25% from the baseline, restarting if the systolic blood
pressure recovers to the baseline after 5 minutes. Immediately after the
amifostine, begin infusion with cisplatin 100 mg/M2, along with suitable
hydration and according to an infusion schedule compatible with the
tolerance of the patient (determined according to the judgement of the
treating physician).

Days 2 through 21: rest. No treatment. Monitor patient for
treatment-related side effects and for evidence of tumor response.

Day 22: Begin next cycle of treatment, if tolerance of chemotherapy
and results of treatment with first cycle have been satisfactory.

*Longer infusion schedules for gemcitabine may be more active,
but probably alsomore toxic- - - -

Gemcitabine/Carboplatin Protocol

Dr. McKee has found that using chemoprotective doses of amifostine
significantly protects against the (sometimes profound) thrombocytopenia which
otherwise tends to occur when carboplatin is used with gemcitabine. Because
carboplatin is so much better tolerated in terms of subjective side effects,
this is Dr. McKee's regimen of choice for gemcitabine/platinum combinations,
switching to cisplatin only if profound thrombocytopenia develops, despite the
use of amifostine and Neumega. Dr. McKee reports that chemoprotective doses
of amifostine are best tolerated when taxane type premeds are utilized.
Usually he uses 32 mg Zofran or 1-2 mg Kytril IV along with 10 mg Decadron,
300 mg cimetidine, and 25-50 mg Benadryl. Immediately after the premeds are
administered, he infuses gemcitabine 1 gm/m2 given over 30 minutes in 500 ml
normal saline, which also functions as prehydration for amifostine. 740mg/M2
amifostine is then administered over 10 minutes, monitoring the BP carefully
and holding the infusion for a drop of systolic BP >25% from baseline,
restarting it if the SBP recovers to baseline after 5 min. Immediately after
the amifostine, the carboplatin in an AUC of 5-6 is given over 30 minutes
for doses of 400 mg or less, over 1 hour for doses of more than 400 mg (more
nausea with rapid administration of higher doses). If the platelet count
nadirs below 70,000, consider repeating the amifostine (same dose) after the
carboplatin is administered because of the long half life of carboplatin.
The second dose of amifostine is often transiently emetogenic, less so if
the short acting anti-emetic medications are repeated just prior.

This combination is given x2 cycles q 3 wks, followed by some type of
restaging procedure.